Project title: Pathogenic Role of EPAC1 Signaling in Retinopathy of Prematurity SUMMARY Retinopathy of prematurity (ROP) is the leading cause of vision impair and blindness in the USA in the childhood. Laser photocoagulation is the standard-of-care for treating retinal neovascularization (NV) in ROP, and supplement cryotherapy is occasionally used in severe cases. These treatments only target pathological neovascularization (NV) and have many limitations. There is great need for new strategies and therapies to target other aspects of the disease, including retinal neuronal injury, and promote vascular repair in addition to the control of NV. This study is to determine the role of Epac1 in neuronal injury, pathological NV and physiological vascular repair, and determine the therapeutic effect of Epac inhibitors. Our central hypothesis is that Epac1 activation plays a key causal role in retinal neuronal injury, impairing vascular repair and promoting retinal pathological neovascularization during oxygen-induced retinopathy. This application will, for the first time, use Epac1 global KO mice, Epac1 conditional KO mice and novel Epac inhibitor to investigate the cAMP/Epac1 pathway in retinal neuronal injury, NV and vascular repair. It will address specific contributions of neuronal vs. endothelial Epac1 in these processes, and investigate potential mechanisms of Epac1-induced retinal neuronal and vascular alternations. The research is expected to significantly advance the mechanistic understanding of retinal neurovascular pathologic changes and should facilitate the development of novel strategies to prevent NV, protect retinal neurons and improves vascular repair in ROP.